Method for preparing basic dithienyl compounds

ABSTRACT

Basic dithienyl compounds are prepared by hydrolysis of a compound of the formula ##STR1## wherein R is hydrogen or lower alkyl.

The present invention relates to a novel method for the production ofbasic dithienyl compounds. More particularly, the invention relates to anovel process for the preparation ofl-(+)-α-[1-(3,3-di-3-thienyl-2-propenyl) amino ethyl] benzenemethanolhydrochloride.

Further, the invention relates to a novel precursor ofl-(+)-α-[1-(3,3-di-3-thienyl-2-propenyl) amino ethyl] benzenemethanolhydrochloride and methods for preparing such precursor.

Basic dithienyl compounds are well known pharmacologically activecompounds which are useful in the treatment of heart and circulatoryillnesses. The compounds cause a widening of the coronary vessels andthereby increase the peripheral and cerebral blood flow. This effect isaccompanied in a number of cases by a positive inotropic effect. Thebasic dithienyl compounds are useful in other areas such as curingagents in addition to the human and veterinary medicine fields.

The basic dithienyl compound of the present invention has beenpreviously prepared in accordance with the procedures set out in U.S.Pat. No. 3,766,173 wherein compounds of the formula: ##STR2##

where Y is chlorine, bromine and alkoxy group or a thienyl group and R₁,R₂, R₆ and R₇ are the same or different and are hydrogen or lower alkyl,R₃ is hydrogen or hydroxyl and R₄ and R₅ are the same or different andare hydrogen, halogen, hydroxyalkyl, lower alkyl, lower haloalkyl orlower alkoxy and their pharmacuetically acceptable salts are reactedwith thienyl metal compounds and are converted to the correspondingunsaturated compounds and subsequently converted by known methods to thesalts.

The process for the reaction of the ketone with a thienyl metal compoundis suitable carried out at a temperature between -70° C. and +100° C.While in the preparation of many of the compounds a lower limit of -40°C. is sufficient when the reaction involves a thienyl-(3)-metal compoundthe reaction goes most smoothly below -40° C., for example -70° C. Asthe reaction medium an organic solvent such as dialkyl ethers, e.g.diethylether tetrahydrofuran, hydrocarbons, benzene, etc. can be used.When Y in the formula is thienyl group only one mole of the thienylmetal compound is necessary for the reaction while two moles of thienylcompound are necessary if Y is chlorine, bromine or an alkoxy group. Asthienyl metal compounds thienyl lithium and thienyl grignard compounds,e.g. thienyl magnesium chloride and thienyl magnesium bromide are ofprimary importance.

However, the procedure outlined in U.S. Pat. No. 3,766,172 alwaysrequires an excess of metallo organic compound when active hydrogen ispresent in the reactant.

Moreover, the overall yield of basic dithienyl compound produced via theprior art processes is on the order of about 11%.

I have now found that the overall yield of basic dithienyl compound canbe more than doubled to a yield of on the order of 50% and higher usinga novel cyclic intermediate compound.

In accordance with the present invention, the basic dithienyl compound:

l-(+)-α-[1-(3,3-di-3-thienyl-2-propenyl) amino ethyl] benzenemethanolhydrochloride

is produced when the new compounds of the formula: ##STR3## wherein R ishydrogen, lower alkyl or branched chain lower alkyl of from 1-6 carbonatoms is subjected to hydrolysis.

The precursor of the novel intermediate compounds of the presentinvention is an oxazolidine propionic acid alkyl ester which is obtainedby reacting an alkyl acrylate and l-norphedrine in a appropriate organicsolvent such as toluene, THF, alcohols, benzene, ethyl ether,hydrocarbons, etc, at ambient temperature and pressure for about 24hours. Thereafter an aldehyde of the formula

    RCHO

wherein R is H. lower alkyl of from 1 to 6 carbon atoms or branchedchain lower alkyl of from 1 to 6 carbon atoms, is added to the reactionmixture and the mixture is heated to remove the water formed. When nomore water can be removed, the solution is concentrated and distilled toobtain the oxazolidine propionic acid methyl ester.

The oxazolidine propionic acid methyl ester is subsequently reacted withtwo moles of the reaction product of 3-bromo thiophene and n-butyllithium at reduced temperatures to obtainα,α,(di-3-thienyl)-4-methyl-5-phenyl-2-isopropyl-3-oxazolidine propanolwhich is recovered and hydrolyzed tol-(+)-α-[1-(3,3-di-3-thienyl-2-propenyl) amino ethyl] benzenemethanolhydrochloride.

The novel intermediate compounds of the invention as well as the basicthienyl compounds can be conveniently prepared according to thefollowing synthetic route. ##STR4##

The following examples serve to illustrate the preferred methods ofpreparation and are given by way of illustration only and in no eventare to be construed as limiting.

EXAMPLE 1 4-METHYL-5-PHENYL-2-ISOPROPYL-3-OXAZOLIDINE PROPIONIC ACIDMETHYLESTER (COMPOUND I)

100 ml. of toluene, 43 g. (0.5 moles) of methyl acrylate and 76 g. (0.5moles) of l-norephedrine are added to a 500 ml. three neck flask andstirred at room temperature for 24 hours. To the solution is added 50.4g. (0.7 mole) of isobutyraldehyde and the mixture is heated to removethe water formed, by azeotropic distillation. When no more water can beremoved, concentrate and distill. The oxazolidine propionic acidmethylester boils at 140°-160° C./0.5 mm. The yield is 129 g. (87%) n²³_(d) =1.5020.

EXAMPLE 2 α,α(di-3-thienyl)-4-METHYL-5-PHENYL-2-ISOPROPYL-3-OXAZOLIDINEPROPANOL (COMPOUND II)

Add 163 g. (1.0 moles) of 3-bromo thiophene in 600 ml. of anhydrousether to a three liter three neck flask equipped with a stirrer,dropping funnel and dry ice condenser. Sweep the flask with nitrogen andwith good stirring, drip in 64 g. (1.0 mole) of n-butyllithium (1.6 M inhexane) while keeping the reaction temperature at -60° to -70° C. withdry ice/acetone bath. Stir an additional one half hour at -70° C. whilea solid precipitates. Add 125 g. (0.43 mole) of Compound 1 keeping thetemperature -60° to -70° C., and stir for 15 minutes at -70° C. Removethe dry ice bath and continue stirring while the temperature slowlyrises to 0° C. (11/2 hours). Decompose the reaction mixture by the slowaddition of 500 ml. of water, never letting the temperature go above 25°C. Separate the organic layer and wash with 500 ml. of water.Concentrate the organic layer in vacuo on a steam bath to an oil, coolto 50° C. and add 500 ml. of hexane to crystallize. Filter and dry, theyield is 134 g. (73%), M.P. 125°-7° C.

calc. for C₂₄ H₂₉ NO₂ S₂ :

Theory: C=67.45%; H=6.79%; N=3.28%; S=14.99%:

Found: C=67.76%; H=6.97%; N=3.17%; S=14.27%:

EXAMPLE 3 l-(+)-α-[1-(3,3-di-3-THIENYL-2-PROPENYL) AMINOETHYL]BENEZENEMETHANOL HYDROCHLORIDE (COMPOUND III)

20 g. of Compound II is refluxed with 100 ml. of isopropanol to dissolvethe solid. 30 ml. of 10% aqueous hydrochloric acid is added and thesolution heated to remove isobutraldelyde. As the aldehyde is removed asolid precipitates. Continue to heat for 1/2 hour, add 50 ml. ofisopropanol to the mixture and cool in the refrigerator overnight.Filter and obtain 15.8 g. (86) of Compound III, M.P. 231°-233° C.

The overall yield of Compound III is 56% based on l-norephedrinecompared to the prior art best overall yield of 11%.

EXAMPLE 4 4-METHYL-5-PHENYL-3-OXAZOLIDINE PROPIONIC ACID METHYL ESTER(COMPOUND I)

200 ml. of benzene, 43 g. (0.5 moles) of methyl acrylate and 76 g. ofl-norephedrine are added to a 500 ml. three neck flask and refluxedovernight. To the solution is slowly added 15 g. (0.5 moles) ofparaformaldehyde and the water removed using a dean-stark head.Concentrate the solution in vacuo on a steam bath and distill. Theproduct boils at 137°-139° C./0.5 mm. The yield is 62 g.; n²⁴ d=1.5155.

EXAMPLE 5 l-(+)-α-[1-(3,3-di-3-THIENYL-2-PROPENYL) AMINOETHYL]BENZENEMETHANOL HYDROCHLORIDE (COMPOUND III)

Add 82 g. (0.5 moles) of 3-bromothiophene in 300 ml. of anhydrous etherto a two liter three neck flask equipped with a stirrer, dropping funneland dry ice condenser. Sweep the flask with nitrogen and with goodstirring, drip in 32 g. (0.5 moles) of n-butyllithium (1.6 M in hexane)while keeping the reaction temperature at -60° to -70° C. with a dryice/acetone bath. Stir an additional one half hour at -70° C. Add 62 g.(0.25 moles) of compound of Example 4 dissolved in 100 ml. of anhydrousether keeping the temperature at -60° C. Stir one half hour at -70° C.and remove dry ice bath and allow to warm to 10° C. over two hours.Decompose by the slow addition of 500 ml. of water and separate the twolayers. Wash the organic layer twice with 200 ml. of water andconcentrate to an oil in vacuo on a steam bath. The intermediateoxazolidine is not isolated but is hydrolyzed to Compound III as inExample 3. The yield is 59%.

The foregoing examples and flow chart have been examplary of theinvention only and not to be considered as placing any limitation on theinvention. It is recognized that various departures may be madetherefrom, which are within the scope of the accompanying claims, and donot depart from the principles of the invention.

What is claimed is:
 1. A method for preparing a compound of the formulaand its salts ##STR5## which comprises hydrolyzing a compound of theformula ##STR6## wherein R is hydrogen in lower alkyl.
 2. A methodaccording to claim 1 wherein R is hydrogen.
 3. A method according toclaim 1 wherein R is lower alkyl.
 4. A method according to claim 1wherein said hydrolysis is carried out at elevated temperatures in therange of from about 20° C. to about 150° C.
 5. A method according toclaim 1 wherein said hydrolysis is carried out in the presence of asolvent.